Pathogenesis of Autoimmune disease

Question 1

What is rheumatoid arthritis?

Answer 1

Chronic joint inflammation at the SYNOVIUM (synovial joints) that can result in joint damage

Question 2

What is ankylosing spondylitis?

Answer 2

Form of seronegative spondyloarthropathy (NO antibodies in serum)

Chronic spinal inflammation at the ENTHESIS that can result in spinal fusion/deformity

Question 3

What is Systemic Lupus erythematosus (SLE)?

Answer 3

Form of connective tissue disease

Chronic tissue inflammation (antibodies directed against self-antigens) particularly in joints, skin and kidney

Associated with autoantibodies

Question 4

Which HLA molecules are associated with the 3 diseases?

Answer 4

Rheumatoid arthritis = HLA-DR4 
SLE = HLA-DR3
Ankylosing spondylitis = HLA-B27 (MHC class 2)

Question 5

Which MHC classes are the HLA molecules?

Answer 5

HLA-DR3/4 = MHC Class 2
HLA-B27 = MHC Class 1

Question 6

What is the function of HLA molecules?

Answer 6

Class 1 - expressed in all nucleated cells, presents endogenous (intracellular) antigens, recognised by CD8+ve T cells, results in killing

Class 2 - expressed in antigen-presenting cells, presents exogenous (extracellular) antigens, recognised by CD4+ve T cells, results in antibody response

Question 7

What is the pathogenesis of a HLA-associated disease? Give example

Answer 7

Peptide antigen binds to HLA, triggers T-cell response

e.g. antigen + HLA-DR4 -> CD4+ve T cell response -> Rheumatoid Arthritis

Question 8

What autoantibodies are involved in rheumatoid arthritis?

Answer 8

Rheumatoid Factor

Anti-cyclic citrullinated peptide antibody

Question 9

What autoantibodies are involved in SLE?

Answer 9

Antinuclear Antibodies (ANA) - seen in all SLE cases, but not specific for SLE
Anti-double stranded DNA antibodies (anti-dsDNA) - SPECIFIC for SLE

Question 10

Biochemical findings of Lupus (SLE) patient?

Answer 10

LOW complement levels

HIGH serum anti-dsDNA

Question 11

What are important cytokines in rheumatoid arthritis?

Answer 11

IL-1/2/6

TNF-a

Question 12

Inhibition of which cytokine can be used in treatment for rheumatoid arthritis?

Answer 12

Activated macrophages release TNF-a which has lots of effects including SINOVITIS

IL-1/6 blockade also used

Question 13

What is RANK-L and how is it involved in rheumatoid treatment?

Answer 13

Stimulates osteoclast formation by binding to RANK
Upregulated by TNF-a and IL-1
DENOSUMAB = monoclonal antibody against RANK-L

Question 14

What drugs are used for Lupus and what is their mechanism?

Answer 14

RITUXIMAB = anti-CD20 antibody (used to deplete B-cells)

BELIMUMAB = monoclonal antibody against B cell survival factor BLYS

Question 15

How are prostaglandins involved in rheumatoid therapy?

Answer 15

Glucocorticoids inhibit phospholipase A2 (which normally generates arachidonic acid)

COX inhibitors (NSAID)
inhibit synthesis of prostaglandins (inflammatory mediators) from arachidonic acid

However they are NOT disease modifying - only treats the symptoms